IL-8 receptor antagonists

ABSTRACT

The present invention involves certain 8-ureido and 8-thioureido, 1,2-benzothiazines, 1,2,4-benzothioxazines and 1,2,4-benzothiodiazines useful in the treatment of disease states mediated by the chemokine, Interleukin-8.

The present application claims priority to the PCT US98/02608 filed Feb.12, 1998 and U.S. provisional application 60/037,609 filed Feb. 12,1997.

FIELD OF THE INVENTION

This invention relates to novel cyclic substituted compounds,pharmaceutical compositions, processes for their preparation, and usethereof in treating IL-8, GROα, GROβ, GROγ, NAP-2, and ENA-78 mediateddiseases.

BACKGROUND OF THE INVENTION

Many different names have been applied to Interleukin-8 (IL-8), such asneutrophil attractant/activation protein-1 (NAP-1), monocyte derivedneutrophil chemotactic factor (MDNCF), neutrophil activating factor(NAF), and T-cell lymphocyte chemotactic factor. Interleukin-8 is achemoattractant for neutrophils, basophils, and a subset of T-cells. Itis produced by a majority of nucleated cells including macrophages,fibroblasts, endothelial and epithelial cells exposed to TNF, IL-1a,IL-1b or LPS, and by neutrophils themselves when exposed to LPS orchemotactic factors such as FMLP. M. Baggiolini et al., J. Clin. Invest.84, 1045 (1989); J. Schroder et al, J. Immunol. 139, 3474 (1987) and J.Immunol. 144, 2223 (1990); Strieter, et al., Science 243, 1467 (1989)and J. Biol. Chem. 264, 10621 (1989); Cassatella et al., J. Immunol.148, 3216 (1992).

GROα, GROβ, GROγand NAP-2 also belong to the chemokine a family. LikeIL-8 these chemokines have also been referred to by different names. Forinstance GROα, β, γ have been referred to as MGSAa, b and g respectively(Melanoma Growth Stimulating Activity), see Richmond et al., J. CellPhysiology 129, 375 (1986) and Chang et al., J. Immunol 148, 451 (1992).All of the chemokines of the a-family which possess the ELR motifdirectly preceding the CXC motif bind to the IL-8 B receptor.

IL-8, GROα, GROβ, GROγ, NAP-2, and ENA-78 stimulate a number offunctions in vitro. They have all been shown to have chemoattractantproperties for neutrophils, while IL-8 and GROα have demonstratedT-lymphocytes, and basophilic chemotactic activity. In addition IL-8 caninduce histamine release from basophils from both normal and atopicindividuals GRO-α and IL-8 can in addition, induce lysozomal enzymerelease and respiratory burst from neutrophils. IL-8 has also been shownto increase the surface expression of Mac-1 (CD11b/CD18) on neutrophilswithout de novo protein synthesis. This may contribute to increasedadhesion of the neutrophils to vascular endothelial cells. Many knowndiseases are characterized by massive neutrophil infiltration. As IL-8,GROα, GROβ, GROγ and NAP-2 promote the accumulation and activation ofneutrophils, these chemokines have been implicated in a wide range ofacute and chronic inflammatory disorders including psoriasis andrheumatoid arthritis, Baggiolini et al., FEBS Lett. 307, 97 (1992);Miller et al., Crit. Rev. Immunol. 12, 17 (1992); Oppenheim et al.,Annu. Rev. Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87,463 (1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992);Donnely et al., Lancet 341, 643 (1993). In addition the ELR chemokines(those containing the amino acids ELR motif just prior to the CXC motif)have also been implicated in angiostasis. Strieter et al., Science 258,1798 (1992).

In vitro, IL-8, GROα, GROβ, GROγ and NAP-2 induce neutrophil shapechange, chemotaxis, granule release, and respiratory burst, by bindingto and activating receptors of the seven-transmembrane, G-protein-linkedfamily, in particular by binding to IL-8 receptors, most notably theB-receptor. Thomas et al., J. Biol. Chem. 266, 14839 (1991); and Holmeset al., Science 253, 1278 (1991). The development of non-peptide smallmolecule antagonists for members of this receptor family has precedent.For a review see R. Freidinger in: Progress in Drug Research, Vol. 40,pp. 33-98, Birkhauser Verlag, Basel 1993. Hence, the IL-8 receptorrepresents a promising target for the development of novelanti-inflammatory agents.

Two high affinity human IL-8 receptors (77% homology) have beencharacterized: IL-8Ra, which binds only IL-8 with high affinity, andIL-8Rb, which has high affinity for IL-8 as well as for GROα, GROβ, GROγand NAP-2. See Holmes et al., supra; Murphy et al., Science 253, 1280(1991); Lee et al., J. Biol. Chem. 267, 16283 (1992); LaRosa et al., J.Biol. Chem. 267, 25402 (1992); and Gayle et al., J. Biol. Chem. 268,7283 (1993).

There remains a need for treatment, in this field, for compounds whichare capable of binding to the IL-8 a or b receptor. Therefore,conditions associated with an increase in IL-8 production (which isresponsible for chemotaxis of neutrophil and T-cells subsets into theinflammatory site) would benefit by compounds which are inhibitors ofIL-8 receptor binding.

SUMMARY OF THE INVENTION

This invention provides for a method of treating a chemokine mediateddisease, wherein the chemokine is one which binds to an IL-8 a or breceptor and which method comprises administering an effective amount ofa compound of Formula (I) or (II) or a pharmaceutically acceptable saltthereof. In particular the chemokine is IL-8.

This invention also relates to a method of inhibiting the binding ofIL-8 to its receptors in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I) or (II).

The present invention also provides for the novel compounds of Formula(I), and (II) and pharmaceutical compositions comprising a compound ofFormula (I), and (II) and a pharmaceutical carrier or diluent.

Compounds of Formula (I) useful in the present invention are representedby the structure:

wherein

R is —NH—C(X₁)—NH—(CR₁₃R₁₄)_(v)—Z;

X₁ is oxygen or sulfur;

Z is W, HET,

 an optionally substituted C₁₋₁₀ alkyl, an optionally substituted C₂₋₁₀alkenyl, or an optionally substituted C₂₋₁₀ alkynyl;

X is N—R₁₈, O, C(O) or C(R₁₉)₂;

R₁ is independently selected from hydrogen, halogen, nitro, cyano,halosubstituted C₁₋₁₀ alkyl, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₁₋₁₀ alkoxy,halosubstituted C₁₋₁₀ alkoxy, (CR₈R₈)_(q)S(O)_(t)R₄, hydroxy, hydroxyC₁₋₄alkyl, aryl, aryl C₁₋₄ alkyl, aryloxy, aryl C₁₋₄ alkyloxy,heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic C₁₋₄alkyl,heteroaryl C₁₋₄ alkyloxy, aryl C₂₋₁₀ alkenyl, heteroaryl C₂₋₁₀ alkenyl,heterocyclic C₂₋₁₀ alkenyl, (CR₈R₈)_(q)NR₄R₅, C₂₋₁₀ alkenyl C(O)NR₄R₅,(CR₈R₈)_(q)C(O)NR₄R₅, (CR₈R₈)_(q)C(O)NR₄R₁₀, S(O)₃R₈,(CR₈R₈)_(q)C(O)R₁₁, C₂₋₁₀ alkenyl C(O)R₁₁, C₂₋₁₀ alkenyl C(O)OR₁₁,C(O)R₁₁, (CR₈R₈)_(q)C(O)OR₁₂, (CR₈R₈)_(q)OC(O) R₁₁,(CR₈R₈)_(q)NR₄C(O)R₁₁, (CR₈R₈)_(q)C(NR₄)NR₄R₅, (CR₈R₈)_(q)NR₄C(NR₅)R₁₁,(CR₈R₈)_(q)NHS(O)₂R₁₇, or (CR₈R₈)_(q)S(O)₂NR₄R₅; or two R₁ moietiestogether may form O—(CH₂)_(s)—O or a 5 to 6 membered saturated orunsaturated ring; and wherein the aryl, heteroaryl, and heterocycliccontaining moieties may all be optionally substituted;

n is an integer having a value of 1 to 3;

m is an integer having a value of 1 to 3;

p is an integer having a value of 1 to 3;

q is 0, or an integer having a value of 1 to 10;

s is an integer having a value of 1 to 3;

t is 0, or an integer having a value of 1 or 2;

v is 0, or an integer having a value of 1 to 4;

HET is an optionally substituted heteroaryl;

R₄ and R₅ are independently hydrogen, optionally substituted C₁₋₄ alkyl,optionally substituted aryl, optionally substituted aryl C₁₋₄alkyl,optionally substituted heteroaryl, optionally substituted heteroarylC₁₋₄alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl, or R₄ and R₅ togetherwith the nitrogen to which they are attached form a 5 to 7 member ringwhich may optionally comprise an additional heteroatom selected fromO/N/S;

R₆ is independently hydrogen, halogen, C₁₋₁₀ alkoxy, optionallysubstituted C₁₋₄ alkyl, halosubstituted C₁₋₄ alkyl, optionallysubstituted aryl, optionally substituted aryl C₁₋₄alkyl, optionallysubstituted heteroaryl, optionally substituted heteroaryl C₁₋₄alkyl,optionally substituted heterocyclic, or optionally substitutedheterocyclic C₁₋₄ alkyl;

Y is independently selected from hydrogen, halogen, nitro, cyano,halosubstituted C₁₋₁₀ alkyl, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₁₋₁₀ alkoxy,halosubstituted C₁₋₁₀ alkoxy, (CR₈R₈)_(q)S(O)_(t)R₄, hydroxy,hydroxyC₁₋₄alkyl, aryl, aryl C₁₋₄ alkyl, aryloxy, arylC₁₋₄ alkyloxy,heteroaryl, heteroarylalkyl, heteroaryl C₁₋₄ alkyloxy, heterocyclic,heterocyclic C₁₋₄alkyl, aryl C₂₋₁₀ alkenyl, heteroaryl C₂₋₁₀ alkenyl,heterocyclic C₂₋₁₀ alkenyl, (CR₈R₈)_(q)NR₄R₅, C₂₋₁₀ alkenyl C(O)NR₄R₅,(CR₈R₈)_(q)C(O)NR₄R₅, (CR₈R₈)_(q)C(O)NR₄R₁₀, S(O)₃R₈;(CR₈R₈)_(q)C(O)R₁₁, C₂₋₁₀ alkenyl C(O)R₁₁, C₂₋₁₀ alkenyl C(O)OR₁₁,(CR₈R₈)_(q)C(O)OR₁₂, (CR₈R₈)_(q)OC(O) R₁₁, (CR₈R₈)_(q)NR₄C(O)R₁₁,(CR₈R₈)qC(NR₄)NR₄R₅, (CR₈R₈)_(q)NR₄C(NR₅)R₁₁, (CR₈R₈)_(q NHS(O)) ₂R_(a),or (CR₈R₈)_(q)S(O)₂NR₄R₅; or two Y moieties together may formO—(CH₂)_(s)—O or a 5 to 6 membered saturated or unsaturated ring; andwherein the aryl, heteroaryl, and heterocyclic containing moieties mayall be optionally substituted;

R₈ is hydrogen or C₁₋₄ alkyl;

R₁₀ is C₁₋₁₀ alkyl C(O)₂R₈;

R₁₁ is hydrogen, C₁₋₄ alkyl, optionally substituted aryl, optionallysubstituted aryl C₁₋₄alkyl, optionally substituted heteroaryl,optionally substituted heteroarylC₁₋₄alkyl, optionally substitutedheterocyclic, or optionally substituted heterocyclicC₁₋₄alkyl;

R₁₂ is hydrogen, C₁₋₁₀ alkyl, optionally substituted aryl or optionallysubstituted arylalkyl;

R₁₃ and R₁₄ are independently hydrogen, optionally substituted C₁₋₄alkyl, or one of R₁₃ and R₁₄ may be optionally substituted aryl;

R₁₅ and R₁₆ are independently hydrogen or an optionally substituted C₁₋₄alkyl,

R₁₇ is C₁₋₄ alkyl, optionally substituted aryl, optionally substitutedaryl C₁₋₄alkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylC₁₋₄alkyl, optionally substituted heterocyclic, oroptionally substituted heterocyclicC 1 4alkyl;

R₁₈ is hydrogen, optionally substituted C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy,halosubstituted C₁₋₁₀ alkoxy, hydroxy, arylC₁₋₄ alkyl, arylC₂₋₄ alkenyl,heteroaryl, heteroaryl-C₁₋₄alkyl, heteroarylC₂₋₄ alkenyl, heterocyclic,or heterocyclicC₁₋₄ alkyl, wherein the aryl, heteroaryl and heterocycliccontaining moieties may all be optionally substituted;

R₁₉ is independently hydrogen, halogen, C₁₋₁₀ alkyl, NR₄R₅, C₁₋₁₀alkyl-NR₄R_(5, C(O)NR) ₄R₅, optionally substituted C₁₋₁₀ alkyl,halosubstituted C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halosubstituted C₁₋₁₀ alkoxy,hydroxy, aryl, aryl C₁₋₄ alkyl, aryloxy, aryl C₁₋₄ alkyloxy, heteroaryl,heteroarylalkyl, heterocyclic, heterocyclic C₁₋₄alkyl, or heteroarylC₁₋₄ alkyloxy;

R_(a) is NR₄R₅, alkyl, arylC₁₋₄ alkyl, arylC₂₋₄ alkenyl, heteroaryl,heteroaryl-C₁₋₄alkyl, heteroarylC₂₋₄ alkenyl, heterocyclic, orheterocyclicC₁₋₄ alkyl; and wherein the aryl, heteroaryl andheterocyclic containing moieties may all be optionally substituted;

W is

 the E containing ring is optionally selected from

the asterix * denoting point of attachment of the ring;

or a pharmaceutically acceptable salt thereof.

Compounds of Formula (II) useful in the present invention arerepresented by the structure:

wherein

R is —NH—C(X₁)—NH—(CR₁₃R₁₄)_(v)—Z;

X₁ is oxygen or sulfur;

Z is W, HET,

 an optionally substituted C₁₋₁₀ alkyl, an optionally substituted C₂₋₁₀alkenyl, or an optionally substituted C₂₋₁₀ alkynyl;

X is N, or CR₆;

R₁ is independently selected from hydrogen, halogen, nitro, cyano,halosubstituted C₁₋₁₀ alkyl, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₁₋₁₀ alkoxy,halosubstituted C₁₋₁₀ alkoxy, (CR₈R₈)_(q)S(O)_(t)R₄, hydroxy, hydroxyC₁₋₄alkyl, aryl, aryl C₁₋₄ alkyl, aryloxy, aryl C₁₋₄ alkyloxy,heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic C₁₋₄alkyl,heteroaryl C₁₋₄ alkyloxy, aryl C₂₋₁₀ alkenyl, heteroaryl C₂₋₁₀ alkenyl,heterocyclic C₂₋₁₀ alkenyl, (CR₈R₈)_(q)NR₄R₅, C₂₋₁₀ alkenyl C(O)NR₄R₅,(CR₈R₈)_(q)C(O)NR₄R₅, (CR₈R₈)_(q)C(O)NR₄R₁₀, S(O)₃R₈,(CR₈R₈)_(q)C(O)R₁₁, C₂₋₁₀ alkenyl C(O)R₁₁, C₂₋₁₀ alkenyl C(O)OR₁₁,C(O)R₁₁, (CR₈R₈)_(q)C(O)OR₁₂, (CR₈R₈)_(q)OC(O) R₁₁,(CR₈R₈)_(q)NR₄C(O)R₁₁, (CR₈R₈)_(q)C(NR₄)NR₄R₅, (CR₈R₈)_(q)NR₄C(NR₅)R₁₁,(CR₈R₈)_(q)NHS(O)₂R₁₇, or (CR₈R₈)_(q)S(O)₂NR₄R₅; or two R₁ moietiestogether may form O—(CH₂)_(s)O or a 5 to 6 membered saturated orunsaturated ring; and wherein the aryl, heteroaryl, and heterocycliccontaining moieties may all be optionally substituted;

n is an integer having a value of 1 to 3;

m is an integer having a value of 1 to 3;

p is an integer having a value of 1 to 3;

q is 0, or an integer having a value of 1 to 10;

s is an integer having a value of 1 to 3;

t is 0, or an integer having a value of 1 or 2;

v is 0, or an integer having a value of 1 to 4;

HET is an optionally substituted heteroaryl;

R₄ and R₅ are independently hydrogen, optionally substituted C₁₋₄ alkyl,optionally substituted aryl, optionally substituted aryl C₁₋₄alkyl,optionally substituted heteroaryl, optionally substituted heteroarylC₁₋₄alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl, or R₄ and R₅ togetherwith the nitrogen to which they are attached form a 5 to 7 member ringwhich may optionally comprise an additional heteroatom selected fromO/N/S;

R₆ is hydrogen, halogen, C₁₋₁₀ alkoxy, optionally substituted C₁₋₄alkyl, halosubstituted C₁₋₄ alkyl, optionally substituted aryl,optionally substituted aryl C₁₋₄alkyl, optionally substitutedheteroaryl, optionally substituted heteroaryl C₁₋₄alkyl, optionallysubstituted heterocyclic, or optionally substituted heterocyclic C₁₋₄alkyl;

Y is independently selected from hydrogen, halogen, nitro, cyano,halosubstituted C₁₋₁₀ alkyl, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₁₋₁₀ alkoxy,halosubstituted C₁₋₁₀ alkoxy, (CR₈R₈)_(q)S(O)_(t)R₄, hydroxy,hydroxyC₁₋₄alkyl, aryl, aryl C₁₋₄ alkyl, aryloxy, arylC₁₋₄ alkyloxy,heteroaryl, heteroarylalkyl, heteroaryl C₁₋₄ alkyloxy, heterocyclic,heterocyclic C₁₋₄alkyl, aryl C₂₋₁₀ alkenyl, heteroaryl C₂₋₁₀ alkenyl,heterocyclic C₂₋₁₀ alkenyl, (CR₈R₈)_(q)NR₄R₅, C₂₋₁₀ alkenyl C(O)NR₄R₅,(CR₈R₈)_(q)C(O)NR₄R₅, (CR₈R₈)_(q)C(O)NR₄R₁₀, S(O)₃R₈,(CR₈R₈)_(q)C(O)R₁₁, C₂₋₁₀ alkenyl C(O)R₁₁, C₂₋₁₀ alkenyl C(O)OR₁₁,(CR₈R₈)_(q)C(O)OR₁₂, (CR₈R₈)_(q)OC(O)R₁₁, (CR₈R₈)_(q)NR₄C(O)R₁₁,(CR₈R₈)_(q)C(NR₄)NR₄R₅, (CR₈R₈)_(q)NR₄C(NR₅)R₁₁,(CR₈R₈)_(q)NHS(O)₂R_(a), or (CR₈R₈)_(q)S(O)₂NR₄R₅; or two Y moietiestogether may form O—(CH₂)_(s)O or a 5 to 6 membered saturated orunsaturated ring; and wherein the aryl, heteroaryl, and heterocycliccontaining moieties may all be optionally substituted;

R₈ is hydrogen or C₁₋₄ alkyl;

R₁₀ is C₁₋₁₀ alkyl C(O)₂R₈;

R₁₁ is hydrogen, C₁₋₄ alkyl, optionally substituted aryl, optionallysubstituted aryl C₁₋₄alkyl, optionally substituted heteroaryl,optionally substituted heteroarylC₁₋₄alkyl, optionally substitutedheterocyclic, or optionally substituted heterocyclicC₁₋₄alkyl;

R₁₂ is hydrogen, C₁₋₁₀ alkyl, optionally substituted aryl or optionallysubstituted arylalkyl;

R₁₃ and R₁₄ are independently hydrogen, optionally substituted C₁₋₄alkyl, or one of R₁₃ and R₁₄ may be optionally substituted aryl;

R₁₇ is C₁₋₄ alkyl, optionally substituted aryl, optionally substitutedaryl C₁₋₄alkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylC₁₋₄alkyl, optionally substituted heterocyclic, oroptionally substituted heterocyclic C₁₋₄alkyl;

R₁₈ is hydrogen, optionally substituted C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy,halosubstituted C₁₋₁₀ alkoxy, hydroxy, arylC₁₋₄ alkyl, arylC₂₋₄ alkenyl,heteroaryl, heteroaryl-C₁₋₄alkyl, heteroarylC₂-₄ alkenyl, heterocyclic,or heterocyclicC₁₋₄ alkyl, wherein the aryl, heteroaryl and heterocycliccontaining moieties may all be optionally substituted;

R₁₉ is independently hydrogen, halogen, C₁₋₁₀ alkyl, NR₄R₅, C₁₋₁₀ alkylNR₄R_(5, C(O)NR) ₄R₅, optionally substituted C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy,halosubstituted C₁₋₁₀ alkoxy, hydroxy, aryl, aryl C₁₋₄ alkyl, aryloxy,aryl C₁₋₄ alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic,heterocyclic C₁₋₄alkyl, or heteroaryl C₁₋₄ alkyloxy;

R_(a) is NR₄R₅, alkyl, arylC₁₋₄ alkyl, arylC₂₋₄ alkenyl, heteroaryl,heteroaryl-C₁₋₄alkyl, heteroarylC₂₋₄ alkenyl, heterocyclic, orheterocyclicC₁₋₄ alkyl; and wherein the aryl, heteroaryl andheterocyclic containing moieties may all be optionally substituted;

W is

 the E containing ring is optionally selected from

the asterix * denoting point of attachment of the ring;

or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of Formula (I) and (II) may also be used in associationwith the veterinary treatment of mammals, other than. humans, in need ofinhibition of IL-8 or other chemokines which bind to the IL-8 α and βreceptors. Chemokine mediated diseases for treatment, therapeutically orprophylactically, in animals include disease states such as those notedherein in the Methods of Treatment section.

As readily seen, the difference between compounds of Formula (I) and(II) lies in the unsaturation of the hetero containing ring, and hencethe substitutions on the X and the double bond. The remaining terms,defined below, are the same for both compounds of Formula (I) and (II)unless otherwise indicated.

Suitably R₁ is independently selected from hydrogen; halogen; nitro;cyano; halosubstituted C₁₋₁₀ alkyl, such as CF₃; C₁₋₁₀ alkyl, such asmethyl, ethyl, isopropyl, or n-propyl; C₂₋₁₀ alkenyl; C₁₋₁₀ alkoxy, suchas methoxy, or ethoxy; halosubstituted C₁₋₁₀ alkoxy, such astrifluoromethoxy; azide; (CR₈R₈)_(q)S(O)_(t)R₄, wherein t is 0, 1 or 2;hydroxy; hydroxy C₁₋₄alkyl, such as methanol or ethanol; aryl, such asphenyl or naphthyl; aryl C₁₋₄ alkyl, such as benzyl; aryloxy, such asphenoxy; aryl C₁₋₄ alkyloxy, such as benzyloxy; heteroaryl;heteroarylalkyl; heteroaryl C₁₋₄ alkyloxy; aryl C₂₋₁₀ alkenyl;heteroaryl C₂₋₁₀ alkenyl; heterocyclic C₂₋₁₀ alkenyl; (CR₈R₈)_(q)NR₄R₅;C₂₋₁₀ alkenyl C(O)NR₄R₅; (CR₈R₈)_(q)C(O)NR₄R₅; (CR₈R₈)_(q)C(O)NR₄R₁₀;S(O)₃H; S(O)₃R₈; (CR₈R₈)_(q)C(O)R₁₁; C₂₋₁₀ alkenyl C(O)R₁₁; C₂₋₁₀alkenyl C(O)OR₁₁; C(O)R₁₁; (CR₈R₈)_(q)C(O)OR₁₂; (CR₈R₈)_(q)OC(O)RI 1;(CR₈R₈)_(q)NR₄C(O)R₁₁; (CR₈R₈)_(q)C(NR₄)NR₄R₅; (CR₈R₈)_(q)NR₄C(NR₅)R₁₁;(CR₈R₈)_(q)NHS(O)₂R₁₇; (CR₈R₈)_(q)S(O)₂NR₄R₅; or two R₁ moietiestogether may form O—(CH₂)_(s)—O or a 5 to 6 membered saturated orunsaturated ring. All of the aryl, heteroaryl, and heterocycliccontaining moieties may be optionally substituted as defined hereinbelow.

For use herein the term “the aryl, heteroaryl, and heterocycliccontaining moieties” refers to both the ring and the alkyl, or ifincluded, the alkenyl rings, such as aryl, arylalkyl, and aryl alkenylrings. The term “moieties” and “rings” may be interchangeably usedthroughout.

It is recognized that R₁ moiety may be substituted on either the benzenering or the X containing ring, if possible.

When R₁ forms a dioxybridge, s is preferably 1. When R₁ forms anadditional unsaturated ring, it is preferably 6 membered resulting in anaphthylene ring system. This naphthylene ring may be substitutedindependently, 1 to 3 times by the other R₁ moieties as defined above.

Suitably, R₄ and R₅ are independently hydrogen, optionally substitutedC₁₋₄ alkyl, optionally substituted aryl, optionally substituted arylC₁₋₄alkyl, optionally substituted heteroaryl, optionally substitutedheteroaryl C₁₋₄alkyl, heterocyclic, heterocyclicC₁₋₄ alkyl, or R₄ and R₅together with the nitrogen to which they are attached form a 5 to 7member ring which may optionally comprise an additional heteroatomselected from O/N/S.

Suitably, R₈ is independently hydrogen or C₁₋₄ alkyl.

Suitably, q is 0 or an integer having a value of 1 to 10.

Suitably, R₁₀ is C₁₋₁₀ alkyl C(O)₂R₈, such as CH₂C(O)₂H or CH₂C(O)₂CH₃.

Suitably, R₁₁ is hydrogen, C₁₋₄ alkyl, aryl, aryl C₁₋₄ alkyl,heteroaryl, heteroaryl C₁₋₄alkyl, heterocyclic, or heterocyclicC₁₋₄alkyl.

Suitably, R₁₂ is hydrogen, C₁₋₁₀ alkyl, optionally substituted aryl oroptionally substituted arylalkyl.

Suitably, R₁₃ and R₁₄ are independently hydrogen, or an optionallysubstituted C₁₋₄ alkyl which may be straight or branched as definedherein, or one of R₁₃ and R₁₄ are an optionally substituted aryl.

Suitably, v is 0, or an integer having a value of 1 to 4.

When R₁₃ or R₁₄ are an optionally substituted alkyl, the alkyl moietymay be substituted one to three times independently by halogen;halosubstituted C₁₋₄ alkyl such as trifluoromethyl; hydroxy; hydroxyC₁₋₄alkyl; C₁₋₄ alkoxy; such as methoxy, or ethoxy; halosubstitutedC₁₋₁₀ alkoxy; S(O)_(t)R₄; aryl; NR₄R₅; NHC(O)R₄; C(O)NR₄R₅; or C(O)OR₈.

Suitably, R₁₇ is C₁₋₄alkyl, aryl, arylalkyl, heteroaryl,heteroarylC₁₋₄alkyl, heterocyclic, or heterocyclicC₁₋₄alkyl, wherein allof the aryl, heteroaryl and heterocyclic containing moieties may all beoptionally substituted.

Suitably, Y is independently selected from hydrogen; halogen; nitro;cyano; halosubstituted C₁₋₁₀ alkyl; C₁₋₁₀ alkyl; C₂₋₁₀ alkenyl; C₁₋₁₀alkoxy; halosubstituted C₁₋₁₀ alkoxy; azide; (CR₈R₈)_(q)S(O)_(t)R₄;hydroxy; hydroxyC₁₋₄alkyl; aryl; aryl C₁₋₄ alkyl; aryloxy; arylC₁₋₄alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C₁₋₄ alkyloxy;heterocyclic, heterocyclic C₁₋₄alkyl; aryl C₂₋₁₀ alkenyl; heteroarylC₂₋₁₀ alkenyl; heterocyclic C₂₋₁₀ alkenyl; (CR₈R₈)_(q)NR₄R₅; C₂₋₁₀alkenyl C(O)NR₄R₅; (CR₈R₈)_(q)C(O)NR₄R₅; (CR₈R₈)_(q)C(O)NR₄R₁₀; S(O)₃H;S(O)₃R₈; (CR₈R₈)_(q)C(O)R₁₁; C₂₋₁₀ alkenyl C(O)R₁₁; C₂₋₁₀ alkenylC(O)OR₁₁; (CR₈R₈)_(q)C(O)OR₁₂; (CR₈R₈)_(q)OC(O) R₁₁;(CR₈R₈)_(q)C(NR₄)NR₄R₅; (CR₈R₈)_(q)NR₄C(NR₅)R₁₁; (CR₈R₈)_(q)NR₄C(O)R₁₁;(CR₈R₈)_(q)NHS(O)₂R_(a); or (CR₈R₈)_(q)S(O)₂NR₄R₅; or two Y moietiestogether may form O—(CH₂)_(s)—O or a 5 to 6 membered saturated orunsaturated ring. The aryl, heteroaryl and heterocyclic containingmoieties noted above may all be optionally substituted as definedherein.

When Y forms a dioxybridge, s is preferably 1. When Y forms anadditional unsaturated ring, it is preferably 6 membered resulting in anaphthylene ring system. These ring systems may be substituted 1 to 3times by other Y moieties as defined above.

Suitably, R_(a) is NR₄R₅, alkyl, aryl C₁₋₄ alkyl, arylC₂₋₄ alkenyl,heteroaryl, heteroaryl-C₁₋₄alkyl, heteroarylC₂₋₄ alkenyl, heterocyclic,heterocyclicC₁₋₄ alkyl, wherein all of the aryl, heteroaryl andheterocyclic containing rings may all be optionally substituted.

Y is preferably a halogen, C₁₋₄ alkoxy, optionally substituted aryl,optionally substituted aryloxy or arylalkoxy, methylene dioxy, NR₄R₅,thio C₁₋₄alkyl, thioaryl, halosubstituted alkoxy, optionally substitutedC₁₋₄ alkyl, or hydroxy alkyl. Y is more preferably mono-substitutedhalogen, disubstituted halogen, mono-substituted alkoxy, disubstitutedalkoxy, methylenedioxy, aryl, or alkyl, more preferably these groups aremono or di-substituted in the 2′- position or 2′-, 3′-position.

While Y may be substituted in any of the ring positions, n is preferablyone. While both R₁ and Y can both be hydrogen, it is preferred that atleast one of the rings be substituted, preferably both rings aresubstituted.

In compounds of Formula (I), R is —NH—C(X₁)—NH—(CR₁₃R₁₄)_(v)—Z.

Suitably, Z is W, HET,

an optionally substituted C₁₋₁₀ alkyl, an optionally substituted C₂₋₁₀alkenyl, or an optionally substituted C₂₋₁₀ alkynyl.

Suitably, p is an integer having a value of 1 to 3.

X₁ is oxygen or sulfur, preferably oxygen.

Suitably when Z is a heteroaryl (HET) ring, it is suitably a heteroarylring or ring system. If the HET moiety is a multi ring system, the ringcontaining the heteroatom does not need to be directly attached to theurea moiety through the (R₁₃R₁₄)_(v) linkage. Any of the ring(s) inthese systems may be optionally substituted as defined herein.Preferably the HET moiety is a pyridyl, which may be 2-, 3- or4-pyridyl. If the ring is a multi system ring it is preferablybenzimidazole, dibenzothiophene, or an indole ring. Other rings ofinterest include, but are not limited to thiophene, furan, pyrimidine,pyrrole, pyrazole, quinoline, isoquinoline, quinazolinyl, oxazole,thiazole, thiadiazole, triazole, imidazole, or benzimidazole.

The HET ring may be optionally substituted independently one to five,preferably 1 to 3 times by Y as defined above. The substitutions may bein any of the ring(s) of the HET system, such as in a benzimidazolering.

Suitably R₁₅ and R₁₆ are independently hydrogen, or an optionallysubstituted C₁₋₄ alkyl as defined above for R₁₃ and R₁₄.

Suitably, W is

Suitably, the E containing ring is optionally selected from

the asterix * denoting point of attachment of the ring.

The E ring denoted by its point of attachment through the asterix (*)may optionally be present. If it is not present the ring is a phenylmoiety which is substituted by the R₁ terms as shown. The E ring may besubstituted by the (Y)n moiety in any ring, saturated or unsaturated,and is shown for purposes herein substituted only in the unsaturatedring(s).

While Y in the W term may be substituted in any of the 5 ring positionsof the phenyl moiety (when E is absent), Y is preferablymono-substituted in the 2′- position or 3′- position, with the 4′-preferably being unsubstituted. If the phenyl ring is disubstituted,substituents are preferably in the 2′or 3′ position of a monocyclicring. While both R₁ and Y can both be hydrogen, it is preferred that atleast one of the rings be substituted, preferably both rings aresubstituted.

Suitably, for compounds of Formula (I), X is N—R₁₈, O, C(O) or C(R₁₉)₂.

Suitably, R₁₈ is hydrogen, optionally substituted C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, halosubstituted C₁₋₁₀ alkoxy, hydroxy, arylC₁₋₄ alkyl, arylC₂₋₄alkenyl, heteroaryl, heteroaryl-C₁₋₄alkyl, heteroarylC₂₋₄ alkenyl,heterocyclic, or heterocyclicC₁₋₄ alkyl, wherein the aryl, heteroaryland heterocyclic containing moieties may all be optionally substituted.Preferably, for compounds of formula (I), R₁₈ is hydrogen or alkyl, morepreferably hydrogen.

Suitably, R₁₉ is independently hydrogen, halogen, C₁₋₁₀ alkyl, NR₄R₅,C₁₋₁₀ alkyl-NR₄R₅, C(O)NR₄R₅, optionally substituted C₁₋₁₀ alkyl,halosubstituted C₁₋₁₀ alkyl C₁₋₁₀ alkoxy, halosubstituted C₁₋₁₀ alkoxy,hydroxy, aryl, aryl C₁₋₄ alkyl, aryloxy, aryl C₁₋₄ alkyloxy, heteroaryl,heteroarylalkyl, heterocyclic, heterocyclic C₁₋₄alkyl, or heteroarylC₁₋₄ alkyloxy;

For compounds of Formula (II) X is N, or CR₆.

Suitably, R₆ is hydrogen, halogen, C₁₋₁₀ alkoxy, optionally substitutedC₁₋₄ alkyl, halosubstituted C₁₋₄ alkyl, optionally substituted aryl,optionally substituted aryl C₁₋₄alkyl, optionally substitutedheteroaryl, optionally substituted heteroaryl C₁₋₄alkyl, optionallysubstituted heterocyclic, or an optionally substituted heterocyclic C₁₋₄alkyl.

As used herein, “optionally substituted” unless specifically definedshall mean such groups as halogen, such as fluorine, chlorine, bromineor iodine; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy, suchas methoxy or ethoxy; S(O)_(m′)C₁₋₁₀ alkyl, wherein m′ is 0, 1 or 2,such as methyl thio, methyl sulfinyl or methyl sulfonyl; amino, mono &di-substituted amino, such as in the NR₄R₅ group; NHC(O)R₄; C(O)NR₄R₅;C(O)OH; S(O)₂NR₄R₅; NHS(O)₂R₂₀, C₁₋₁₀ alkyl, such as methyl, ethyl,propyl, isopropyl, or t-butyl; halosubstituted C₁₋₁₀ alkyl, such CF₃; anoptionally substituted aryl, such as phenyl, or an optionallysubstituted arylalkyl, such as benzyl or phenethyl, optionallysubstituted heterocylic, optionally substituted heterocyclicalkyl,optionally substituted heteroaryl, optionally substituted heteroarylalkyl, wherein these aryl , heteroaryl, or heterocyclic moieties may besubstituted one to two times by halogen; hydroxy; hydroxy substitutedalkyl; C₁₋₁₀ alkoxy; S(O)_(m′)C₁₋₁₀ alkyl; amino, mono & di-substitutedamino, such as in the NR₄R₅ group; C₁₋₁₀ alkyl, or halosubstituted C₁₋₁₀alkyl, such as CF₃.

R₂₀ is suitably C₁₋₄ alkyl, aryl, aryl C₁₋₄alkyl, heteroaryl,heteroarylC₁₋₄alkyl, heterocyclic, or heterocyclicC₁₋₄alkyl.

Suitable pharmaceutically acceptable salts are well known to thoseskilled in the art and include basic salts of inorganic and organicacids, such as hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methane sulphonic acid, ethane sulphonic acid, aceticacid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,phenylacetic acid and mandelic acid. In addition, pharmaceuticallyacceptable salts of compounds of Formula (I) may also be formed with apharmaceutically acceptable cation, for instance, if a substituent groupcomprises a carboxy moiety. Suitable pharmaceutically acceptable cationsare well known to those skilled in the art and include alkaline,alkaline earth, ammonium and quaternary ammonium cations.

The following terms, as used herein, refer to:

“halo”—all halogens, that is chloro, fluoro, bromo and iodo.

“C₁₋₁₀alkyl” or “alkyl”—both straight and branched chain radicals of 1to 10 carbon atoms, unless the chain length is otherwise limited,including, but not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like.

The term “cycloalkyl” is used herein to mean cyclic radicals, preferablyof 3 to 8 carbons, including but not limited to cyclopropyl,cyclopentyl, cyclohexyl, and the like.

The term “alkenyl” is used herein at all occurrences to mean straight orbranched chain radical of 2-10 carbon atoms, unless the chain length islimited thereto, including, but not limited to ethenyl, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.

“aryl”—phenyl and naphthyl;

“heteroaryl” (on its own or in any combination, such as “heteroaryloxy”,or “heteroaryl alkyl”)—a 5-10 membered aromatic ring system in which oneor more rings contain one or more heteroatoms selected from the groupconsisting of N, O or S, such as, but not limited, to pyrrole, pyrazole,furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine,pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, orbenzimidazole.

“heterocyclic” (on its own or in any combination, such as“heterocyclicalkyl”)—a saturated or partially unsaturated 4-10 memberedring system in which one or more rings contain one or more heteroatomsselected from the group consisting of N, O, or S; such as, but notlimited to, pyrrolidine, piperidine, piperazine, morpholine,tetrahydropyran, or imidazolidine.

The term “arylalkyl” or “heteroarylalkyl” or “heterocyclicalkyl” is usedherein to mean C₁₋₁₀ alkyl, as defined above, attached to an aryl,heteroaryl or heterocyclic moiety, as also defined herein, unlessotherwise indicated.

“sulfinyl”—the oxide S(O) of the corresponding sulfide, the term “thio”refers to the sulfide, and the term “sulfonyl” refers to the fullyoxidized S(O)₂ moiety.

The term “wherein two R₁ moieties (or two Y moieties) may together forma 5 or 6 membered saturated or unsaturated ring” is used herein to meanthe formation of an aromatic ring system, such as naphthalene, or is aphenyl moiety having attached a 6 membered partially saturated orunsaturated ring such as a C₆ cycloalkenyl, i.e. hexene, or a C₅cycloalkenyl moiety, such as cyclopentene.

Exemplified compounds of Formula (I) include:

N-[8-(3,4-Dihydro-1H-2,1-benzothiazine,2,2-dioxide)]-N′-[2-bromophenyl]urea;

N-[8-(4-Keto-3,4-dihydrosulfostyril)]-N′(2-bromophenyl)urea

Exemplified compounds of Formula (II) include:

N-[8-(Sulfostyril)]-N′-[2-bromophenyl]urea

For purposes herein the ring systems for compounds of Formula (I) and(II) are named as follows for illustration only with v=0, and Z isphenyl:

For compounds of Formula (I):

X=N, X₁=O, v=0, and Z is an unsubstituted phenyl

N-(3,4-Dihydro-2,2-dioxido-1H-2,1,4-benzothiadiazin-8-yl)-N′-phenylurea

X=N, X₁=S, v=0, and Z is an unsubstituted phenyl

N-(3,4-Dihydro-2,2-dioxido-1H-2,1,4-benzothiadiazin-8-yl)-N′-phenylthiourea

X=C, X₁=O, v=0, and Z is an unsubstituted phenyl

N-(3,4-Dihydro-2,2-dioxido-1H-2,1-benzothiazin-8-yl)-N′-phenylurea

X=C, X₁=S, v=0, and Z is an unsubstituted phenyl

N-(3,4-Dihydro-2,2-dioxido-1H-2,1-benzothiazin-8-yl)-N′-phenylthiourea

X=C(=O) i.e. carbonyl, X₁=O, v=0, and Z is an unsubstituted phenyl

N-(3,4-Dihydro-2,2-dioxido-4-oxo-1H-2,1-benzothiazin-8-yl)-N′-phenylurea

X=C(=O) i.e. carbonyl, X₁=S, v=0, and Z is an unsubstituted phenyl

N-(3,4-Dihydro-2,2-dioxido-4-oxo-1H-2,1-benzothiazin-8-yl)-N′-phenylthiourea

For compounds of Formula (II):

wherein

X=N, X₁=O, v=0, and Z is an unsubstituted phenyl

N-(2,2-Dioxido-1H-2,1,4-benzothiadiazin-8-yl)-N′-phenylurea

X=N, X₁=S, v=0, and Z is an unsubstituted phenyl

N-(2,2-Dioxido-1H-2,1,4-benzothiadiazin-8-yl)-N′-phenylthiourea

X=C, X₁=O, v=0, and Z is an unsubstituted phenyl

N-(2,2-Dioxido-1H-2,1-benzothiazin-8-yl)-N′-phenylurea

X=C, X₁=S, v=0, and Z is an unsubstituted phenyl

N-(2,2-Dioxido-1H-2,1-benzothiazin-8-yl)-N′-phenylthiourea

Methods of Preparation

The compounds of Formula (I) and (II) may be obtained by applyingsynthetic procedures, some of which are illustrated in the Schemesbelow. The synthesis provided for in these Schemes is applicable for theproducing of Formula (I) having a variety of different R, R₁, and Argroups which are reacted, employing optional substituents which aresuitably protected to achieve compatibility with the reactions outlinedherein. Subsequent deprotection, in those cases, then affords compoundsof the nature generally disclosed. Once the urea nucleus has beenestablished, further compounds of these formulas may be prepared byapplying standard techniques for functional group interconversion, wellknown in the art. While the schemes are shown with compounds of Formula(I) this is merely for illustration purposes only.

If the desired heterocyclic compound 6-scheme 1 is not commerciallyavailable, the commercially available sulfonic acid can be converted tothe corresponding sulfonyl chloride using a chlorinating agent such asthionyl chloride. The thionyl chloride 2-scheme 1 can be reacted with acommercially available aniline. The ester can be hydrolyzed using basicconditions such as 10% NaOH. The acid 3-scheme 1 can be cyclized underacidic or lewis acidic conditions such as polyphosphoric acid or AlCl₃.The ketone can be converted to the double bond through formation of thehydrazine followed by rearrangement to the double bond under basicconditions. If substitution is desired on the sulfonamide ring it can beproduced by alkylation of the compound 4-scheme-1 using standardconditions such as reaction with an alkyl halide in the presence of abase. The acidic nitrogen on compound 4-scheme-1 may have to betemporarily protected with a suitable protecting group such as an allyl,sulfonamide or BOM group.(Green ref) Alternatively compound 6-scheme-1can be functionalized using a Michael reaction involving afunctionalized organo cuprate. A number of other reactions can also beused to functionalize the double bond such epoxidation followed byepoxide opening, bromination followed by alkylation, and Diels-Alderreactions.

If the desired aniline 3-scheme 2 is not commercially available thecorresponding nitro compound can be prepared from 1-scheme 2, understandard nitration conditions (using HNO₃ or NaNO₃) at 23° C. The nitrocompound can then be reduced to the corresponding aniline using SnCl₂ inEtOH. (or alternately LiAlH₄).

If the desired aniline 2-scheme 3 is not commercially available thenitro compound can be prepared from 2-scheme 2, which can then bereduced to the corresponding aniline using H₂/Pd in EtOH.

Ortho substituted heterocyclic phenyl ureas in 2-scheme 4 may beprepared by standard conditions involving the condensation of thecommercially available optionally substituted (aryl or alkyl) isocyanateor thioisocyanate (Aldrich Chemical Co., Milwaukee, Wis.) with thecorresponding aniline 1-scheme 4 in an aprotic solvent such as (DMF,toluene).

If the desired heterocyclic compound 3-scheme 5 is not commerciallyavailable then it can be prepared by condensing the commerciallyavailable sulfonyl chloride 2-scheme 1 with 2-nitro aniline followed byhydrolysis to the acid 2-scheme 5. The acid can be cyclized by treatmentwith SOCl₂ then AlCl₃ in CH₂Cl₂. The corresponding aniline and the orthosubstituted phenyl urea may be prepared using conditions outlined inscheme 2 and scheme 4.

If the desired heterocycle 3-Scheme 6 is not available it can besynthesized from the corresponding commercially available amino phenoland chloromethyl sulfonyl chloride under basic conditions(such astriethyl amine or potassium carbonate). The corresponding aniline andthe ortho substituted phenyl urea may be prepared using conditionsoutlined in scheme 2 and scheme 4. If substitution is desired on thesulfonamide ring it can be produced by alkylation of the compound3-scheme-6 using standard conditions such as reaction with an alkylhalide in the presence of a base. The acidic nitrogen on compound3-scheme-6 may have to be protected with a suitable protecting groupsuch as an allyl, sulfonamide or BOM group.

If the desired heterocycle 3-Scheme 7 is not available in can besynthesized from the corresponding commercially availablephenylenediamine and chloromethyl sulfonyl chloride under basicconditions(such as triethyl amine or potassium carbonate). Thecorresponding aniline and the ortho substituted phenyl urea may beprepared using conditions outlined in scheme 2 and scheme 4. Ifsubstitution is desired on the sulfonamide ring it can be produced byalkylation of the compound 3-scheme-7 using standard conditions such asreaction with an alkyl halide in the presence of a base. The acidicnitrogen on compound 3-scheme-7 may have to be protected with a suitableprotecting group such as an allyl, sulfonamide or BOM group. In the casewhere R₁₈ is H the compound 3-scheme-7 can be oxidized to the imineusing MnO₂.

SYNTHETIC EXAMPLES

The invention will now be described by reference to the followingexamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention. All temperatures aregiven in degrees centigrade, all solvents are highest available purityand all reactions run under anhydrous conditions in an argon atmosphereunless otherwise indicated.

In the Examples, all temperatures are in degrees Centigrade (° C). Massspectra were performed upon a VG Zab mass spectrometer using fast atombombardment, unless otherwise indicated. ¹H-NMR (hereinafter “NMR”)spectra were recorded at 250 MHz using a Bruker AM 250 or Am 400spectrometer. Multiplicities indicated are: s=singlet, d=doublet,t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat.indicates a saturated solution, eq indicates the proportion of a molarequivalent of reagent relative to the principal reactant.

Example 1 Preparation of N-[8-(Sulfostyril)]-N′-[2-bromophenyl]urea

a) Preparation of Methyl Chlorosulfonyl Acetate

To a solution of sulfoacetic acid(10 g, 71.4 mmol) in 30% benzene inmethanol(100 ml), the anhydrous hydrogen chloride was passed through thesolution for 4 hours. The solution was then heated to reflux temperatureand water was collected in a Dean-Stark trap. After the distillatecleared to one phase the solution was stirred at reflux for 1 hour. Thenit was cooled to room temperature and concentrated. The residue wasdissolved in thionyl chloride(12.3 g, 71.4 mmol) and was stirred at 120°C. for 3 hours. Then all solvent evaporated to give desired product(11g, 93.5%). ¹H NMR (CDCL₃): δ 4.62 (s, 2H), 3.89 (s, 3H).

b) Preparation of Methyl N-Phenylsulfamoylacetate

To a solution of aniline (84.5 g, 910 mmol) in anhydrous ether (1 L),the methyl chlorosulfonyl acetate (74.7 g, 433 mmol) was added dropwiseat below 10° C. The reaction mixture was stirred at room temperature for20 hours and then filtered. The filtrate was concentrated andchromatography of the resulting solid on silica gel (50% Ethylacetate/Hexane) gave the desired product(64 g, 64%). mp 76-78° C.

c) Preparation of N-Phenylsulfamoylacetic Acid

A solution of methyl N-phenylsulfonylacetate (17.9 g, 78.2 mmol) in 10%sodium hydroxide (180 ml) was heated for 3 hours at refluxedtemperature. The solution was cooled and acidified with 3N ofhydrochloric acid. The resulting solid was extracted with chloroform andthe combined the organic layer was dried (MgSO₄) and concentrated togive the desired product (9.2 g, 55%). mp 113-115° C.

d) Preparation of 4-Keto-3,4-dihydrosulfostyril

A mixture of N-phenylsulfamoylacetic acid (2.8 g, 13 mmol) andpolyphosphoric acid (65 g) was heated to 125° C. and maintained at thistemperature for 5 minutes with stirring. The resulting mixture wascooled and poured into 300 ml of ice water. A tan solid precipitated,filtered to give desired product (1.9 g, 74%). mp 192-193° C.

e) Preparation of 4-Keto-3,4-dihydrosulfostyril,p-Toluenesulfonylhydrazone

A mixture of 4-keto-3,4-dihydrosulfostyril (11.3 g, 57.3 mmol),p-toluenesulfonylhydrazine (11.7 g, 63 mmol), alcohol (100 ml) and 3drops of concentrated hydrochloric acid was heated at reflux for 3hours. The resulting mixture was concentrated to 40 ml and then pouredinto 400 ml of ice water. The gum which first separated slowlycrystallized. The solid was filtered and recrystallized fromalcohol-water to give desired product. mp 213-214° C.

f) Preparation of Sulfostyril

To a solution of hydrazone (18.8 g, 51.5 mmol) in hot alcohol (600 ml),sodium methoxide (8.65 g, 155 mmol) was added. The reaction mixture wasstirred at refluxed temperature for several minutes until precipitatewas complete. Sufficient water was added to dissolve the solid, and theresulting brown solution was stirred at reflux for 20 hours. Thesolution was concentrated to a small volume then diluted with water. Onacidification with concentrated hydrochloric acid a precipitateseparated and was filtered. The solid was extracted twice with boilingwater, on cooling, a white solid precipitated and this wasrecrystallized from chloroform to give desired product. (4.5 g, 48.4%).mp 153-155° C.

g) Preparation of 8-Nitrosulfostyril

Sulfostyril (1.0 g, 5.52 mmol) was dissolved in methylene chloride (40ml) followed by the addition of sodium nitrate (0.516 g, 6.1 mmol). Theaddition of sulfuric acid (1.1 ml/3M) is then made, followed by additionof a catalytic amount of sodium nitrite. The mixture is allowed to stir.After 24 hours, the reaction mixture is diluted with methylene chlorideand extracted with water. The organic layer is dried over MgSO₄ andfiltered. The solvent was evaporated and chromatography of the resultingsolid on silica gel (4% MeOH/CH₂Cl₂) gave the desired product(260 mg,21%). EI-MS m/z 227 (M⁺).

h) Preparation of 8-Aminosulfostyril

To the solution of 8-nitrosulfostyril (130 mg, 0.57 mmol) in ethanol (10ml), Tin (II) chloride (688 mg, 3.05 mmol) was added. The reactionmixture was stirred at refluxed temperature for 4 hours. Then was cooledto room temperature. The NaHCO₃ (aq) was added to pH=7. Then wasextracted with ethyl acetate (3×). The combined organic layer was driedover MgSO₄, filtered and concentrated under reduced pressure to givedesired product (105 mg, 94%). EI-MS m/z 197 (M⁻).

i) N-[8-(Sulfostyril)]-N′-[2-bromophenyl]urea

To a solution of 2-bromo phenyl isocyanate (26 mg, 0.13 mmol) in DMF(1.0 ml), the 8-aminosulfostyril (24 mg, 0.12 mmol) was added. Thereaction mixture was stirred at room temperature for 16 hours.Chromatography of the resulting liquid on silica gel (50% Ethylacetate/Hexane) gave desired product (26 mg, 54%). EI-MS m/z 395 (M⁺).

Example 2

Preparation ofN-[8-(3,4-Dihydro-1H-2,1-benzothiazine,2.2-dioxide)]-N′-[2-bromophenyl]urea

a) Preparation of 8-Amino-(3,4-Dihydro-1H-2,1-benzothiazine,2,2-dioxide

To a solution of 8-nitrosulfostyril (130 mg, 0.57 mmol) in ethanol(15ml) and was added 10% Pd/C (130 mg). The mixture was flushed with argon,then the solution was stirred with a hydrogen atmosphere at balloonpressure for 2 hours. The mixture was filtered through celite and thecelite was washed with ethanol. The solvent was evaporated to give thedesired product(64 mg, 58%). EI-MS m/z 199 (M⁺).

b) Preparation ofN-[8-(3,4-Dihydro-1H-2,1-benzothiazine,2.2-dioxide)]-N′-[2-bromophenyl]urea

To a solution of 2-bromo phenyl isocyanate (74.8 mg, 0.37 mmol) in DMF(1.0 ml), the 8-amino-(3,4-Dihydro-1H-2,1-benzothiazine, 2,2-dioxide (68mg, 0.34 mmol) was added. The reaction mixture was stirred at roomtemperature for 16 hours. Chromatography of the resulting liquid onsilica gel (50% Ethyl acetate/Hexane) gave desired product (80 mg,58.8%). EI-MS m/z 397 (M⁺).

Using analagous methods to those indicated above, the followingadditional compounds may be synthesized:

Example 3 N-[8-(4-Keto-3,4-dihydrosulfostyril)]-N′(2-bromophenyl)urea:EI-MS m/z 408(M−H)⁻. Method of Treatment

The compounds of Formula (I), (II) or a pharmaceutically acceptable saltthereof can be used in the manufacture of a medicament for theprophylactic or therapeutic treatment of any disease state in a human,or other mammal, which is exacerbated or caused by excessive orunregulated IL-8 cytokine production by such mammal's cell, such as butnot limited to monocytes and/or macrophages, or other chemokines whichbind to the IL-8 α or β receptor, also referred to as the type I or typeII receptor.

For purposes herein, ther term “a compound of Formula (I)” alsorepresents “compounds of Formula (II)”, unless specifically indicated.

Accordingly, the present invention provides a method of treating achemokine mediated disease, wherein the chemokine is one which binds toan IL-8 α or β receptor and which method comprises administering aneffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof. In particular, the chemokines are IL-8, GROα,GROβ, GROγ, NAP-2 or ENA-78.

The compounds of Formula (I) are administered in an amount sufficient toinhibit cytokine function, in particular IL-8, GROα, GROβ, GROγ, NAP-2or ENA-78, such that they are biologically regulated down to normallevels of physiological function, or in some case to subnormal levels,so as to ameliorate the disease state. Abnormal levels of IL-8, GROα,GROβ, GROγ, NAP-2 or ENA-78 for instance in the context of the presentinvention, constitute: (i) levels of free IL-8 greater than or equal to1 picogram per mL; (ii) any cell associated IL-8, GROα, GROβ GROγ, NAP-2or ENA-78 above normal physiological levels; or (iii) the presence ofIL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 above basal levels in cells ortissues in which IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 respectively,is produced.

There are many disease states in which excessive or unregulated IL-8production is implicated in exacerbating and/or causing the disease.Chemokine mediated diseases include psoriasis, atopic dermatitis,arthritis, asthma, chronic obstructive pulmonary disease, adultrespiratory distress syndrome, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, stroke, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, cardiac and renal reperfusioninjury, glomerulonephritis, thrombosis, graft vs. host reaction,Alzheimer's disease, allograft rejections, malaria, restinosis,angiogenesis or undesired hematopoietic stem cells release.

These diseases are primarily characterized by massive neutrophilinfiltration, T-cell infiltration, or neovascular growth, and areassociated with increased IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78production which is responsible for the chemotaxis of neutrophils intothe inflammatory site or the directional growth of endothelial cells. Incontrast to other inflammatory cytokines (IL-1, TNF, and IL-6), IL-8,GROα, GROβ, GROγ, NAP-2 or ENA-78 has the unique property of promotingneutrophil chemotaxis, enzyme release including but not limited toelastase release as well as superoxide production and activation. Theα-chemokines but particularly, GROα, GROβ, GROγ, NAP-2 or ENA-78,working through the IL-8 type I or II receptor can promote theneovascularization of tumors by promoting the directional growth ofendothelial cells. Therefore, the inhibition of IL-8 induced chemotaxisor activation would lead to a direct reduction in the neutrophilinfiltration.

Recent evidence also implicates the role of chemokines in the treatmentof HIV infections, Littleman et al., Nature 381, pp. 661 (1996) and Koupet al., Nature 381, pp. 667 (1996).

The present invention also provides for a means of treating, in an acutesetting, as well as preventing, in those individuals deemed susceptibleto, CNS injuries by the chemokine receptor antagonist compounds ofFormula (I).

CNS injuries as defined herein include both open or penetrating headtrauma, such as by surgery, or a closed head trauma injury, such as byan injury to the head region. Also included within this definition isischemic stroke, particularly to the brain area.

Ischemic stroke may be defined as a focal neurologic disorder thatresults from insufficient blood supply to a particular brain area,usually as a consequence of an embolus, thrombi, or local atheromatousclosure of the blood vessel. The role of inflammatory cytokines in thisare has been emerging and the present invention provides a mean for thepotential treatment of these injuries. Relatively little treatment, foran acute injury such as these has been available.

TNF-α is a cytokine with proinflammatory actions, including endothelialleukocyte adhesion molecule expression. Leukocytes infiltrate intoischemic brain lesions and hence compounds which inhibit or decreaselevels of TNF would be useful for treatment of ischemic brain injury.See Liu et al., Stoke, Vol. 25. No. 7, pp. 1481-88 (1994) whosedisclosure is incorporated herein by reference.

Models of closed head injuries and treatment with mixed 5-LO/CO agentsis discussed in Shohami et al., J. of Vaisc & Clinical Physiology andPharmacology, Vol. 3, No. 2, pp. 99-107 (1992) whose disclosure isincorporated herein by reference. Treatment which reduced edemaformation was found to improve functional outcome in those animalstreated.

The compounds of Formula (I) are administered in an amount sufficient toinhibit IL-8, binding to the IL-8 alpha or beta receptors, from bindingto these receptors, such as evidenced by a reduction in neutrophilchemotaxis and activation. The discovery that the compounds of Formula(I) are inhibitors of IL-8 binding is based upon the effects of thecompounds of Formulas (I) in the in vitro receptor binding assays whichare described herein. The compounds of Formula (I) and (II) have beenshown to be inhibitors of type II IL-8 receptors.

As used herein, the term “IL-8 mediated disease or disease state” refersto any and all disease states in which IL-8, GROα, GROβ, GROγ, NAP-2 orENA-78 plays a role, either by production of IL-8, GROα, GROβ, GROγ,NAP-2 or ENA-78 themselves, or by IL-8, GROα, GROβ, GROγ, NAP-2 orENA-78 causing another monokine to be released, such as but not limitedto IL-1, IL-6 or TNF. A disease state in which, for instance, IL-1 is amajor component, and whose production or action, is exacerbated orsecreted in response to IL-8, would therefore be considered a diseasestated mediated by IL-8.

As used herein, the term “chemokine mediated disease or disease state”refers to any and all disease states in which a chemokine which binds toan IL-8 α or β receptor plays a role, such as but not limited to IL-8,GRO-α, GRO-β, GROγ, NAP-2 or ENA-78. This would include a disease statein which, IL-8 plays a role, either by production of IL-8 itself, or byIL-8 causing another monokine to be released, such as but not limited toIL-1, IL-6 or TNF. A disease state in which, for instance, IL-1 is amajor component, and whose production or action, is exacerbated orsecreted in response to IL-8, would therefore be considered a diseasestated mediated by IL-8.

As used herein, the term “cytokine” refers to any secreted polypeptidethat affects the functions of cells and is a molecule which modulatesinteractions between cells in the immune, inflammatory or hematopoieticresponse. A cytokine includes, but is not limited to, monokines andlymphokines, regardless of which cells produce them. For instance, amonokine is generally referred to as being produced and secreted by amononuclear cell, such as a macrophage and/or monocyte. Many other cellshowever also produce monokines, such as natural killer cells,fibroblasts, basophils, neutrophils, endothelial cells, brainastrocytes, bone marrow stromal cells, epideral keratinocytes andB-lymphocytes. Lymphokines are generally referred to as being producedby lymphocyte cells. Examples of cytokines include, but are not limitedto, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8),Tumor Necrosis Factor-alpha (TNF-α) and Tumor Necrosis Factor beta(TNF-β).

As used herein, the term “chemokine” refers to any secreted polypeptidethat affects the functions of cells and is a molecule which modulatesinteractions between cells in the immune, inflammatory or hematopoieticresponse, similar to the term “cytokine” above. A chemokine is primarilysecreted through cell transmembranes and causes chemotaxis andactivation of specific white blood cells and leukocytes, neutrophils,monocytes, macrophages, T-cells, B-cells, endothelial cells and smoothmuscle cells. Examples of chemokines include, but are not limited to,IL-8, GRO-α, GRO-β, GRO-γ, NAP-2, ENA-78, IP-10, MIP-1α, MIP-β, PF4, andMCP 1, 2, and 3.

In order to use a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof in therapy, it will normally be formulated intoa pharmaceutical composition in accordance with standard pharmaceuticalpractice. This invention, therefore, also relates to a pharmaceuticalcomposition comprising an effective, non-toxic amount of a compound ofFormula (I) and a pharmaceutically acceptable carrier or diluent.

Compounds of Formula (I), pharmaceutically acceptable salts thereof andpharmaceutical compositions incorporating such may conveniently beadministered by any of the routes conventionally used for drugadministration, for instance, orally, topically, parenterally or byinhalation. The compounds of Formula (I) may be administered inconventional dosage forms prepared by combining a compound of Formula(I) with standard pharmaceutical carriers according to conventionalprocedures. The compounds of Formula (I) may also be administered inconventional dosages in combination with a known, second therapeuticallyactive compound. These procedures may involve mixing, granulating andcompressing or dissolving the ingredients as appropriate to the desiredpreparation. It will be appreciated that the form and character of thepharmaceutically acceptable character or diluent is dictated by theamount of active ingredient with which it is to be combined, the routeof administration and other well-known variables. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like. Similarly, the carrier or diluent may includetime delay material well known to the art, such as glycerylmono-stearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25mg. to about 1 g. When a liquid carrier is used,the preparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampule or nonaqueousliquid suspension.

Compounds of Formula (I) may be administered topically, that is bynon-systemic administration. This includes the application of a compoundof Formula (I) externally to the epidermis or the buccal cavity and theinstillation of such a compound into the ear, eye and nose, such thatthe compound does not significantly enter the blood stream. In contrast,systemic administration refers to oral, intravenous, intraperitoneal andintramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as liniments, lotions, creams, ointmentsor pastes, and drops suitable for administration to the eye, ear ornose. The active ingredient may comprise, for topical administration,from 0.001% to 10% w/w, for instance from 1% to 2% by weight of theFormulation. It may however comprise as much as 10% w/w but preferablywill comprise less than 5% w/w, more preferably from 0.1% to 1% w/w ofthe Formulation.

Lotions according to the present invention include those suitable forapplication to the skin or eye. An eye lotion may comprise a sterileaqueous solution optionally containing a bactericide and may be preparedby methods similar to those for the preparation of drops. Lotions orliniments for application to the skin may also include an agent tohasten drying and to cool the skin, such as an alcohol or acetone,and/or a moisturizer such as glycerol or an oil such as castor oil orarachis oil.

Creams, ointments or pastes according to the present invention aresemi-solid formulations of the active ingredient for externalapplication. They may be made by mixing the active ingredient infinely-divided or powdered form, alone or in solution or suspension inan aqueous or non-aqueous fluid, with the aid of suitable machinery,with a greasy or non-greasy base. The base may comprise hydrocarbonssuch as hard, soft or liquid paraffin, glycerol, beeswax, a metallicsoap; a mucilage; an oil of natural origin such as almond, corn,arachis, castor or olive oil; wool fat or its derivatives or a fattyacid such as steric or oleic acid together with an alcohol such aspropylene glycol or a macrogel. The formulation may incorporate anysuitable surface active agent such as an anionic, cationic or non-ionicsurfactant such as a sorbitan ester or a polyoxyethylene derivativethereof. Suspending agents such as natural gums, cellulose derivativesor inorganic materials such as silicaceous silicas, and otheringredients such as lanolin, may also be included.

Drops according to the present invention may comprise sterile aqueous oroily solutions or suspensions and may be prepared by dissolving theactive ingredient in a suitable aqueous solution of a bactericidaland/or fungicidal agent and/or any other suitable preservative, andpreferably including a surface active agent. The resulting solution maythen be clarified by filtration, transferred to a suitable containerwhich is then sealed and sterilized by autoclaving or maintaining at98-100° C. for half an hour. Alternatively, the solution may besterilized by filtration and transferred to the container by an aseptictechnique. Examples of bactericidal and fungicidal agents suitable forinclusion in the drops are phenylmercuric nitrate or acetate (0.002%),benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).Suitable solvents for the preparation of an oily solution includeglycerol, diluted alcohol and propylene glycol.

Compounds of formula (I) may be administered parenterally, that is byintravenous, intramuscular, subcutaneous intranasal, intrarectal,intravaginal or intraperitoneal administration. The subcutaneous andintramuscular forms of parenteral administration are generallypreferred. Appropriate dosage forms for such administration may beprepared by conventional techniques. Compounds of Formula (I) may alsobe administered by inhalation, that is by intranasal and oral inhalationadministration. Appropriate dosage forms for such administration, suchas an aerosol formulation or a metered dose inhaler, may be prepared byconventional techniques.

For all methods of use disclosed herein for the compounds of Formula(I), and (II) the daily oral dosage regimen will preferably be fromabout 0.01 to about 80 mg/kg of total body weight. The daily parenteraldosage regimen about 0.001 to about 80 mg/kg of total body weight. Thedaily topical dosage regimen will preferably be from 0.1 mg to 150 mg,administered one to four, preferably two or three times daily. The dailyinhalation dosage regimen will preferably be from about 0.01 mg/kg toabout 1 mg/kg per day. It will also be recognized by one of skill in theart that the optimal quantity and spacing of individual dosages of acompound of Formula (I) or a pharmaceutically acceptable salt thereofwill be determined by the nature and extent of the condition beingtreated, the form, route and site of administration, and the particularpatient being treated, and that such optimums can be determined byconventional techniques. It will also be appreciated by one of skill inthe art that the optimal course of treatment, i.e., the number of dosesof a compound of Formula (I) or a pharmaceutically acceptable saltthereof given per day for a defined number of days, can be ascertainedby those skilled in the art using conventional course of treatmentdetermination tests.

The invention will now be described by reference to the followingbiological examples which are merely illustrative and are not to beconstrued as a limitation of the scope of the present invention.

BIOLOGICAL EXAMPLES

The IL-8, and Gro-α chemokine inhibitory effects of compounds of thepresent invention are determined by the following in vitro assay:

Receptor Binding Assays:

[¹²⁵I] IL-8 (human recombinant) is obtained from Amersham Corp.,Arlington Heights, Ill., with specific activity 2000 Ci/mmol. Gro-α isobtained from NEN—New England Nuclear. All other chemicals are ofanalytical grade. High levels of recombinant human IL-8 type α and βreceptors were individually expressed in Chinese hamster ovary cells asdescribed previously (Holmes. et al., Science, 1991, 253, 1278). TheChinese hamster ovary membranes were homogenized according to apreviously described protocol (Haour, et al., J Biol Chem., 249 pp2195-2205 (1974)). Except that the homogenization buffer is changed to10 mM Tris-HCL, 1 mM MgSO4, 0.5mM EDTA (ethylene-diaminetetraaceticacid), 1 m MPMSF (α-toluenesulphonyl fluoride), 0.5 mg/L Leupeptin, pH7.5. Membrane protein concentration is determined using Pierce Co.micro-assay kit using bovine serum albumin as a standard. All assays areperformed in a 96-well micro plate format. Each reaction mixturecontains ¹²⁵I IL-8 (0.25 nM) or ¹²⁵I Gro-α and 0.5 μg/mL of IL-8Rα or1.0 μg/mL of IL-8Rβ membranes in 20 mM Bis-Trispropane and 0.4 mM TrisHCl buffers, pH 8.0, containing 1.2 mM MgSO₄, 0.1 mM EDTA, 25 mM NaCland 0.03% CHAPS. In addition, drug or compound of interest is addedwhich has been pre-dissolved in DMSO so as to reach a finalconcentration of between 0.01 nM and 100 μM. The assay is initiated byaddition of ¹²⁵I-IL-8. After 1 hour at room temperature the plate isharvested using a Tomtec 96-well harvester onto a glass fiber filtermatblocked with 1% polyethylenimine/0.5% BSA and washed 3 times with 25 mMNaCl, 10 mM TrisHCI, 1 mM MgSO₄, 0.5 mM EDTA, 0.03% CHAPS, pH 7.4. Thefilter is then dried and counted on the Betaplate liquid scintillationcounter. The recombinant IL-8 Rα, or Type I. receptor is also referredto herein as the non-permissive receptor and the recombinant IL-8 Rβ, orType II, receptor is referred to as the permissive receptor.

Representative compounds of Formula (I), Examples 2 and 3, and ofFormula (II), Example 1, have exhibited positive inhibitory activity inthis assay at IC₅₀ levels<30 um.

Chemotaxis Assay:

The in vitro inhibitory properties of these compounds are determined inthe neutrophil chemotaxis assay as described in Current Protocols inImmunology, vol. I, Suppl 1, Unit 6.12.3., whose disclosure isincorporated herein by reference in its entirety. Neutrophils whereisolated from human blood as described in Current Protocols inImmunology Vol. I, Suppl 1 Unit 7.23.1, whose disclosure is incorporatedherein by reference in its entirety. The chemoattractants IL-8. GRO-α,GRO-β, GRO-γ and NAP-2 are placed in the bottom chamber of a 48multiwell chamber (Neuro Probe, Cabin John, Md.) at a concentrationbetween 0.1 and 100 nM. The two chambers are separated by a 5 umpolycarbonate filter. When compounds of this invention are tested, theyare mixed with the cells (0.001-1000 nM) just prior to the addition ofthe cells to the upper chamber. Incubation is allowed to proceed forbetween about 45 and 90 min. at about 37° C. in a humidified incubatorwith 5% CO₂. At the end of the incubation period, the polycarbonatemembrane is removed and the top side washed, the membrane then stainedusing the Diff Quick staining protocol (Baxter Products, McGaw Park,Ill., USA). Cells which have chemotaxed to the chemokine are visuallycounted using a microscope. Generally, four fields are counted for eachsample, these numbers are averaged to give the average number of cellswhich had migrated. Each sample is tested in triplicate and eachcompound repeated at least four times. To certain cells (positivecontrol cells) no compound is added, these cells represent the maximumchemotactic response of the cells. In the case where a negative control(unstimulated) is desired, no chemokine is added to the bottom chamber.The difference between the positive control and the negative controlrepresents the chemotactic activity of the cells.

Elastase Release Assay:

The compounds of this invention are tested for their ability to preventElastase release from human neutrophils. Neutrophils are isolated fromhuman blood as described in Current Protocols in Immunology Vol. 1,Suppl 1 Unit 7.23.1. PMNs 0.88×10⁶ cells suspended in Ringer's Solution(NaCl 118, KCl 4.56, NaHCO3 25, KH2PO4 1.03, Glucose 11.1, HEPES 5 mM,pH 7.4) are placed in each well of a 96 well plate in a volume of 50 ul.To this plate is added the test compound (0.001-1000 nM) in a volume of50 ul, Cytochalasin B in a volume of 50 ul (20 ug/ml) and Ringers bufferin a volume of 50 ul. These cells are allowed to warm (37° C., 5% CO2,95% RH) for 5 min. before IL-8, GROα, GROβ, GROγ or NAP-2 at a finalconcentration of 0.01-1000 nM was added. The reaction is allowed toproceed for 45 min. before the 96 well plate is centrifuged (800×g 5min.) and 100 ul of the supernatant removed. This supernatant is addedto a second 96 well plate followed by an artificial elastase substrate(MeOSuc-Ala-Ala-Pro-Val-AMC, Nova Biochem, La Jolla, Calif.) to a finalconcentration of 6 ug/ml dissolved in phosphate buffered saline.Immediately, the plate is placed in a fluorescent 96 well plate reader(Cytofluor 2350, Millipore, Bedford, Mass.) and data collected at 3 min.intervals according to the method of Nakajima et al J. Biol. Chem. 2544027 (1979). The amount of Elastase released from the PMNs is calculatedby measuring the rate of MeOSuc-Ala-Ala-Pro-Val-AMC degradation.

TNF-α in Traumatic Brain Injury Assay

The present assay provides for examination of the expression of tumornecrosis factor mRNA in specific brain regions which followexperimentally induced lateral fluid-percussion traumatic brain injury(TBI) in rats. Adult Sprague-Dawley rats (n=42) were anesthetized withsodium pentobarbital (60 mg/kg, i.p.) and subjected to lateralfluid-percussion brain injury of moderate severity (2.4 atm.) centeredover the left temporaparietal cortex (n=18), or “sham” treatment(anesthesia and surgery without injury, n=18). Animals are sacrificed bydecapitation at 1, 6 and 24 hr. post injury, brains removed, and tissuesamples of left (injured) parietal cortex (LC), corresponding area inthe contralateral right cortex (RC), cortex adjacent to injured parietalcortex (LA), corresponding adjacent area in the right cortex (RA), lefthippocampus (LH) and right hippocampus (RH) are prepared. Total RNA wasisolated and Northern blot hybridization is performed and quantitatedrelative to an TNF-α positive control RNA (macrophage=100%). A markedincrease of TNF-α mRNA expression is observed in LH (104±17% of positivecontrol, p<0.05 compared with sham), LC (105±21%, p<0.05) and LA (69±8%,p<0.01) in the traumatized hemisphere 1 hr. following injury. Anincreased TNF-α mRNA expression is also observed in LH (46±8%, p<0.05),LC (30±3%, p<0.01) and LA (32±3%, p<0.01) at 6 hr. which resolves by 24hr. following injury. In the contralateral hemisphere, expression ofTNF-α mRNA is increased in RH (46±2%, p<0.01), RC (4±3%) and RA (22±8%)at 1 hr. and in RH (28±11%), RC (7±5%) and (26+6%, p<0.05) at 6 hr. butnot at 24 hr. following injury. In sham (surgery without injury) ornaive animals, no consistent changes in expression of TNF-α mRNA areobserved in any of the 6 brain areas in either hemisphere at any times.These results indicate that following parasagittal fluid-percussionbrain injury, the temporal expression of TNF-α mRNA is altered inspecific brain regions, including those of the non-traumatizedhemisphere. Since TNF-α is able to induce nerve growth factor (NGF) andstimulate the release of other cytokines from activated astrocytes, thispost-traumatic alteration in gene expression of TNF-α plays an importantrole in both the acute and regenerative response to CNS trauma.

CNS Injury Model for IL-β mRNA

This assay characterizes the regional expression of interleukin-1β(IL-1β) mRNA in specific brain regions following experimental lateralfluid-percussion traumatic brain injury (TBI) in rats. AdultSprague-Dawley rats (n=42) are anesthetized with sodium pentobarbital(60 mg/kg, i.p.) and subjected to lateral fluid-percussion brain injuryof moderate severity (2.4 atm.) centered over the left temporaparietalcortex (n=18), or “sham” treatment (anesthesia and surgery withoutinjury). Animals are sacrificed at 1, 6 and 24 hr. post injury, brainsremoved, and tissue samples of left (injured) parietal cortex (LC),corresponding area in the contralateral right cortex (RC), cortexadjacent to injured parietal cortex (LA), corresponding adjacent area inthe right cortex (RA), left hippocampus (LH) and right hippocampus (RH)are prepared. Total RNA is isolated and Northern blot hybridization wasperformed and the quantity of brain tissue IL-1β mRNA is presented aspercent relative radioactivity of IL- 1β positive macrophage RNA whichwas loaded on same gel. At 1 hr. following brain injury, a marked andsignificant increase in expression of IL-1β mRNA is observed in LC(20.0±0.7% of positive control, n=6, p<0.05 compared with sham animal),LH (24.5±0.9%, p<0.05) and LA (21.5±3.1%, p<0.05) in the injuredhemisphere, which remained elevated up to 6 hr. post injury in the LC(4.0±0.4%, n=6, p<0.05) and LH (5.0±1.3%, p<0.05). In sham or naiveanimals, no expression of IL-1β mRNA is observed in any of therespective brain areas. These results indicate that following TBI, thetemporal expression of IL-1β mRNA is regionally stimulated in specificbrain regions. These regional changes in cytokines, such as IL-1β play arole in the post-traumatic.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe are can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore the Examples herein are to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

What is claimed is:
 1. A compound of the formula:

wherein R is —NH—C(X₁)—NH—(CR₁₃R₁₄)_(v)—Z; X₁ is oxygen or sulfur; Z isW,

 an optionally substituted C₁₋₁₀ alkyl, an optionally substituted C₂₋₁₀alkenyl, or an optionally substituted C₂₋₁₀ alkynyl; X is C(O) orC(R₁₉)₂; R₁ is independently selected from hydrogen, halogen, nitro,cyano, halosubstituted C₁₋₁₀ alkyl, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₁₋₁₀alkoxy, halosubstituted C₁₋₁₀ alkoxy, (CR₈R₈)_(q)S(O)_(t)R₄, hydroxy,hydroxy C₁₋₄alkyl, aryl, aryl C₁₋₄ alkyl, aryloxy, aryl C₁₋₄ alkyloxy,heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic C₁₋₄alkyl,heteroaryl C₁₋₄ alkyloxy, aryl C₂₋₁₀ alkenyl, heteroaryl C₂₋₁₀ alkenyl,heterocyclic C₂₋₁₀ alkenyl, (CR₈R₈)_(q)NR₄R₅, C₂₋₁₀ alkenyl C(O)NR₄R₅,(CR₈R₈)_(q)C(O)NR₄R₅, (CR₈R₈)_(q)C(O)NR₄R₁₀, S(O)₃R₈, (CR₈R₈)_(q C(O)R)₁₁, C₂₋₁₀ alkenyl C(O)R₁₁, C₂₋₁₀ alkenyl C(O)OR₁₁, C(O)R₁₁,(CR₈R₈)_(q)C(O)OR₁₂, (CR₈R₈)_(q)OC(O) R₁₁, (CR₈R₈)_(q)NR₄C(O)R₁₁,(CR₈R₈)_(q)C(NR₄)NR₄R₅, (CR₈R₈)_(q)NR₄C(NR₅)R₁₁, (CR₈R₈)_(q)NHS(O)₂R₁₇,or (CR₈R₈)_(q)S(O)₂NR₄R₅; or two R₁ moieties together form O—(CH₂)_(s)—Oor a 5 to 6 membered saturated or unsaturated ring; and wherein thearyl, heteroaryl, and heterocyclic containing moieties may all beoptionally substituted; n is an integer having a value of 1 to 3; m isan integer having a value of 1 to 3; p is an integer having a value of 1to 3; q is 0, or an integer having a value of 1 to 10; s is an integerhaving a value of 1 to 3; t is 0, or an integer having a value of 1 or2; v is 0, or an integer having a value of 1 to 4; R₄ and R₅ areindependently hydrogen, optionally substituted C₁₋₄ alkyl, optionallysubstituted aryl, optionally substituted aryl C₁₋₄alkyl, optionallysubstituted heteroaryl, optionally substituted heteroaryl C₁₋₄alkyl,heterocyclic, heterocyclic C₁₋₄ alkyl, or R₄ and R₅ together with thenitrogen to which they are attached form a 5 to 7 member ring which mayoptionally comprise an additional heteroatom selected from O/N/S; R₆ isindependently hydrogen, halogen, C₁₋₁₀ alkoxy, optionally substitutedC₁₋₄ alkyl, halosubstituted C₁₋₄ alkyl, optionally substituted aryl,optionally substituted aryl C₁₋₄alkyl, optionally substitutedheteroaryl, optionally substituted heteroaryl C₁₋₄alkyl, optionallysubstituted heterocyclic, optionally substituted heterocyclic C₁₋₄ alkylY is independently selected from hydrogen, halogen, nitro, cyano,halosubstituted C₁₋₁₀ alkyl, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₁₋₁₀ alkoxy,halosubstituted C₁₋₁₀ alkoxy, (CR₈R₈)_(q)S(O)_(t)R₄, hydroxy,hydroxyC₁₋₄alkyl, aryl, aryl C₁₋₄ alkyl, aryloxy, arylC₁₋₄ alkyloxy,heteroaryl, heteroarylalkyl, heteroaryl C₁₋₄ alkyloxy, heterocyclic,heterocyclic C₁₋₄alkyl, aryl C₂₋₁₀ alkenyl, heteroaryl C₂₋₁₀ alkenyl,heterocyclic C₂₋₁₀ alkenyl, (CR₈R₈)_(q)NR₄R₅, C₂₋₁₀ alkenyl C(O)NR₄R₅,(CR₈R₈)_(q)C(O)NR₄R₅, (CR₈R₈)_(q)C(O)NR₄R₁₀, S(O)₃R₈;(CR₈R₈)_(q)C(O)R₁₁, C₂₋₁₀ alkenyl C(O)R₁₁, C₂₋₁₀ alkenyl C(O)OR₁₁,(CR₈R₈)_(q)C(O)OR₁₂, (CR₈R₈)_(q)OC(O) R₁₁, (CR₈R₈)_(q)NR₄C(O)R₁₁,(CR₈R₈)_(q)C(NR₄)NR₄R₅, (CR₈R₈)_(q)NR₄C(NR₅)R₁₁,(CR₈R₈)_(q)NHS(O)₂R_(a), or (CR₈R₈)_(q)S(O)₂NR₄R₅; or two Y moietiestogether may form O—(CH₂)_(s)O or a 5 to 6 membered saturated orunsaturated ring; and wherein the aryl, heteroaryl, and heterocycliccontaining moieties may all be optionally substituted; R₈ is hydrogen orC₁₋₄ alkyl; R₁₀ is C₁₋₁₀ alkyl C(O)₂R₈; R₁₁ is hydrogen, C₁₋₄ alkyl,optionally substituted aryl, optionally substituted aryl C₁₋₄alkyl,optionally substituted heteroaryl, optionally substitutedheteroarylC₁₋₄alkyl, optionally substituted heterocyclic, or optionallysubstituted heterocyclicC₁₋₄alkyl; R₁₂ is hydrogen, C₁₋₁₀ alkyl,optionally substituted aryl or optionally substituted arylalkyl; R₁₃ andR₁₄ are independently hydrogen, optionally substituted C₁₋₄ alkyl, orone of R₁₃ and R₁₄ may be optionally substituted aryl; R₁₅ and R₁₆ areindependently hydrogen or an optionally substituted C₁₋₄ alkyl; R₁₇ isC₁₋₄ alkyl, optionally substituted aryl, optionally substituted arylC₁₋₄alkyl, optionally substituted heteroaryl, optionally substitutedheteroarylC₁₋₄alkyl, optionally substituted heterocyclic, or optionallysubstituted heterocyclicC₁₋₄alkyl; R₁₈ is hydrogen, optionallysubstituted C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halosubstituted C₁₋₁₀ alkoxy,hydroxy, arylC₁₋₄ alkyl, arylC₂₋₄ alkenyl, heteroaryl,heteroaryl-C₁₋₄alkyl, heteroarylC₂₋₄ alkenyl, heterocyclic, orheterocyclicC₁₋₄ alkyl, wherein the aryl, heteroaryl and heterocycliccontaining moieties may all be optionally substituted; R₁₉ isindependently hydrogen, halogen, C₁₋₁₀ alkyl, NR₄R₅, C₁₋₁₀ alkyl-NR₄R₅,C(O)NR₄R₅, optionally substituted C₁₋₁₀ alkyl, halosubstituted C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, halosubstituted C₁₋₁₀ alkoxy, hydroxy, aryl, arylC₁₋₄ alkyl, aryloxy, aryl C₁₋₄ alkyloxy, heteroaryl, heteroarylalkyl,heterocyclic, heterocyclic C₁₋₄alkyl, or heteroaryl C₁₋₄alkyloxy; R_(a)is NR₄R₅, alkyl, arylC₁₋₄ alkyl, arylC₂₋₄ alkenyl, heteroaryl,heteroaryl-C₁₋₄alkyl, heteroarylC₂₋₄ alkenyl, heterocyclic, orheterocyclicC₁₋₄ alkyl; and wherein the aryl, heteroaryl andheterocyclic containing moieties may all be optionally substituted; W is

 the E containing ring is optionally selected from

the asterix * denoting point of attachment of the ring; or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1 wherein R₁ is halogen, cyano, nitro, CF₃, C(O)NR₄R₅, alkenylC(O)NR₄R₅, C(O) R₄R₁₀, alkenyl C(O)OR₁₂, heteroaryl, heteroarylalkyl,heteroaryl alkenyl, or S(O)NR₄R₅.
 3. The compound according to claim 1wherein X is C(O).
 4. The compound according to claim 1 wherein X isC(R₁₉)₂.
 5. The compound according to any of claims 1 to 4 wherein Z isW.
 6. The compound according to claim 5 wherein Y is halogen, C₁₋₄alkoxy, optionally substituted aryl, optionally substituted arylalkoxy,methylene dioxy, NR₄R₅, thioC₁₋₄alkyl, thioaryl, halosubstituted alkoxy,optionally substituted C₁₋₄alkyl, or hydroxy alkyl.
 7. The compoundaccording to claim 1 which is: N-[8-(3,4-Dihydro-1H-2,1-benzothiazine,2,2-dioxide)]-N′-[2-bromophenyl] urea;N-[8-(4-Keto-3,4-dihydrosulfostyril)]-N′(2-bromophenyl)urea; or apharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition comprising a compound according to claim 1, and apharmaceutically acceptable carrier or diluent.
 9. A method of treatinga chemokine mediated disease in a mammal in need thereof, wherein thechemokine binds to an IL-8 α or β receptor, which method comprisesadministering to said mammal an effective amount of a compound accordingto claim
 1. 10. The method according to claim 9 wherein the mammal isafflicted with a chemokine mediated disease selected from psoriasis,atopic dermatitis, asthma, chronic obstructive pulmonary disease, adultrespiratory distress syndrome, arthritis, inflammatory bowel disease,Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, stroke, cardiac and renalreperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease,graft vs. host reaction, or allograft rejections.
 11. A compound of theformula:

wherein R is —NH—C(X₁)—NH—(CR₁₃R₁₄)_(v)—Z; X₁ is oxygen or sulfur; Z isW,

 an optionally substituted C₁₋₁₀ alkyl, an optionally substituted C₂₋₁₀alkenyl, or an optionally substituted C₂₋₁₀ alkynyl; X is CR₆; R¹ isindependently selected from hydrogen, halogen, nitro, cyano,halosubstituted C₁₋₁₀ alkyl, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₁₋₁₀ alkoxy,halosubstituted C₁ ₁₀ alkoxy, (CR₈R₈)_(q)S(O)_(t)R₄, hydroxy, hydroxyC₁₋₄alkyl, aryl, aryl C₁₋₄ alkyl, aryloxy, aryl C₁₋₄ alkyloxy,heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic C₁₋₄alkyl,heteroaryl C₁₋₄ alkyloxy, aryl C₂₋₁₀ alkenyl, heteroaryl C₂₋₁₀ alkenyl,heterocyclic C₂₋₁₀ alkenyl, (CR₈R₈)_(q)NR₄R₅, C₂₋₁₀ alkenyl C(O)NR₄R₅,(CR₈R₈)_(q)C(O)NR₄R₅, (CR₈R₈)_(q)C(O)NR₄R₁₀, S(O)₃R₈,(CR₈R₈)_(q)C(O)R₁₁, C₂₋₁₀ alkenyl C(O)R₁₁, C₂₋₁₀ alkenyl C(O)OR₁₁,C(O)R₁₁, (CR₈R₈)_(q)C(O)OR₁₂, (CR₈R₈)_(q) C(O)R₁₁,(CR₈R₈)_(q)NR₄C(O)R₁₁, (CR₈R₈)_(q)C(NR₄)NR₄R₅, (CR₈R₈)_(q)NR₄C(NR₅)R₁₁,(CR₈R₈)_(q)NHS(O)₂R₁₇, or (CR₈R₈)_(q)S(O)₂NR₄R₅; or two R₁ moietiestogether may form O—(CH₂)_(s)O or a aryl, heteroaryl, and heterocycliccontaining moieties may all be optionally substituted; n is an integerhaving a value of 1 to 3; m is an integer having a value of 1 to 3; p isan integer having a value of 1 to 3; q is 0, or an integer having avalue of 1 to 10; s is an integer having a value of 1 to 3; t is 0, oran integer having a value of 1 or 2; v is 0, or an integer having avalue of 1 to 4; R₄ and R₅ are independently hydrogen, optionallysubstituted C₁₋₄ alkyl, optionally substituted aryl, optionallysubstituted aryl C₁₋₄alkyl, optionally substituted heteroaryl,optionally substituted heteroaryl C₁₋₄alkyl, heterocyclic, heterocyclicC₁₋₄ alkyl, or R₄ and R₅ together with the nitrogen to which they areattached form a 5 to 7 member ring which may optionally comprise anadditional heteroatom selected from O/N/S; R₆ is hydrogen, halogen,C₁₋₁₀ alkoxy, optionally substituted C₁₋₄ alkyl, halosubstituted C₁₋₄alkyl, optionally substituted aryl, optionally substituted arylC₁₋₄alkyl, optionally substituted heteroaryl, optionally substitutedheteroaryl C₁₋₄alkyl, optionally substituted heterocyclic, optionallysubstituted heterocyclic C₁₋₄ alkyl; Y is independently selected fromhydrogen, halogen, nitro, cyano, halosubstituted C₁₋₁₀ alkyl, C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₁₋₁₀ alkoxy, halosubstituted C₁₋₁₀ alkoxy,(CR₈R₈)_(q)S(O)_(t)R₄, hydroxy, hydroxyC₁₋₄alkyl, aryl, aryl C₁₋₄ alkyl,aryloxy, arylC₁₋₄ alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl C₁₋₄alkyloxy, heterocyclic, heterocyclic C₁₋₄alkyl, aryl C₂₋₁₀ alkenyl,heteroaryl C₂₋₁₀ alkenyl, heterocyclic C₂₋₁₀ alkenyl, (CR₈R₈)_(q)NR₄R₅,C₂₋₁₀ alkenyl C(O)NR₄R₅, (CR₈R₈)_(q)C(O)NR₄R₅, (CR₈R₈)_(q)C(O)NR₄R₁₀,S(O)₃R₈, (CR₈R₈)_(q)C(O)R₁₁, C₂₋₁₀ alkenyl C(O)R₁₁, C₂₋₁₀ alkenylC(O)OR₁₁, (CR₈R₈)_(q)C(O)OR₁₂, (CR₈R₈)_(q)OC(O)R₁₁,(CR₈R₈)_(q)NR₄C(O)R₁₁, (CR₈R₈)_(q)C(NR₄)NR₄R₅, (CR₈R₈)_(q)NR₄C(NR₅)R₁₁,(CR₈R₈)_(q)NHS(O)₂R_(a), or (CR₈R₈)_(q)S(O)₂NR₄R₅; or two Y moietiestogether may form O—(CH₂)_(s)O or a 5 to 6 membered saturated orunsaturated ring; and wherein the aryl, heteroaryl, and heterocycliccontaining moieties may all be optionally substituted; R₈ is hydrogen orC₁₋₄ alkyl; R₁₀ is C₁₋₁₀ alkyl C(O)₂R₈; R₁₁ is hydrogen, C₁₋₄ alkyl,optionally substituted aryl, optionally substituted aryl C₁₋₄alkyl,optionally substituted heteroaryl, optionally substitutedheteroarylC₁₋₄alkyl, optionally substituted heterocyclic, or optionallysubstituted heterocyclicC₁₋₄alkyl; R₁₂ is hydrogen, C₁₋₁₀ alkyl,optionally substituted aryl or optionally substituted arylalkyl; R₁₃ andR₁₄ are independently hydrogen, optionally substituted C₁₋₄ alkyl, orone of R₁₃ and R₁₄ may be optionally substituted aryl; R₁₅ and R₁₆ areindependently hydrogen or an optionally substituted C₁₋₄ alkyl; R₁₇ isC₁₋₄ alkyl, optionally substituted aryl, optionally substituted arylC₁₋₄ alkyl, optionally substituted heteroaryl, optionally substitutedheteroarylC₁₋₄alkyl, optionally substituted heterocyclic, or optionallysubstituted heterocyclicC₁₋₄alkyl; R₁₈ is hydrogen, optionallysubstituted C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halosubstituted C₁₋₁₀ alkoxy,hydroxy, arylC₁₋₄ alkyl, arylC₂₋₄ alkenyl, heteroaryl,heteroaryl-C₁₋₄alkyl, heteroarylC₂₋₄ alkenyl, heterocyclic, orheterocyclicC₁₋₄ alkyl, wherein the aryl, heteroaryl and heterocycliccontaining moieties may all be optionally substituted; R₁₉ isindependently hydrogen, halogen, C₁₋₁₀ alkyl, NR₄R₅, C₁₋₁₀ alkyl-NR₄R₅,C(O)NR₄R₅, optionally substituted C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy,halosubstituted C₁₋₁₀ alkoxy, hydroxy, aryl, aryl C₁₋₄ alkyl, aryloxy,aryl C₁₋₄ alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic,heterocyclic C₁₋₄alkyl, or heteroaryl C₁₋₄ alkyloxy; R_(a) is NR₄R₅,alkyl, arylC₁₋₄ alkyl, arylC₂₋₄ alkenyl, heteroaryl,heteroaryl-C₁₋₄alkyl, heteroarylC₂₋₄ alkenyl, heterocyclic, orheterocyclicC₁₋₄ alkyl; and wherein the aryl, heteroaryl andheterocyclic containing moieties may all be optionally substituted; W is

 the E containing ring is optionally selected from

the asterix * denoting point of attachment of the ring; or apharmaceutically acceptable salt thereof.
 12. The compound according toclaim 11 wherein R₁ is halogen, cyano, nitro, CF₃, C(O)NR₄R₅, alkenylC(O)NR₄R₅, C(O) R₄R₁₀, alkenyl C(O)OR₁₂, heteroaryl, heteroarylalkyl,heteroaryl alkenyl, or S(O)NR₄R₅.
 13. The compound according to claim 11wherein X is C—R₆.
 14. The compound according to claim 13 wherein R₆ ishydrogen.
 15. The compound according to claim 11 wherein Z is W.
 16. Thecompound according to claim 15 wherein Y is halogen, C₁₋₄ alkoxy,optionally substituted aryl, optionally substituted arylalkoxy,methylene dioxy, NR₄R₅, thioC₁₋₄alkyl, thioaryl, halosubstituted alkoxy,optionally substituted C₁₋₄alkyl, or hydroxy alkyl.
 17. The compoundaccording to claim 1 which is: N-[8-(Sulfostyril)]-N′-[2-bromophenyl]urea, or a pharmaceutically acceptable salt thereof.
 18. Apharmaceutical composition comprising a compound according claim 11, anda pharmaceutically acceptable carrier or diluent.
 19. A method oftreating a chemokine mediated disease in a mammal in need thereof,wherein the chemokine binds to an IL-8 α or β receptor, which methodcomprises administering to said mammal an effective amount of a compoundaccording to claim
 11. 20. The method according to claim 19 wherein themammal is afflicted with a chemokine mediated disease selected frompsoriasis, atopic dermatitis, asthma, chronic obstructive pulmonarydisease, adult respiratory distress syndrome, arthritis, inflammatorybowel disease, Crohn's disease, ulcerative colitis, septic shock,endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke,cardiac and renal reperfusion injury, glomerulonephritis, thrombosis,Alzheimer's disease, graft vs. host reaction, or allograft rejections.